Asthma is an inflammatory disease of the airways, involving antigen-presenting cells, T lymphocytes, mast cells and eosinophils. B lymphocytes have traditionally been viewed as target cells for Th2 cytokines;however, emerging evidence suggests that regulatory types of B cells (Breg) can be induced under inflammatory conditions and that these Breg cells can suppress inflammation and/or enhance tolerance. Sensitized mice demonstrate a biphasic response to antigen, with acute exposure eliciting allergic airway disease but chronic exposure resulting in local inhalational tolerance (LIT), with resolution of airway and lung inflammation but persistence of systemic allergic sensitization. A consistent feature of LIT is the persistence of lymphocytes in bronchoalveolar lavage, lung tissue, and hilar lymph nodes (HLN). Some of these lymphocytes are regulatory T cells (Treg), but others are B cells. Based on our preliminary data, we hypothesize that a novel regulatory B-cell phenotype differentiates during the development of LIT in regional tissues, and that this cell regulates local immunologic responses. We propose to identify the B cell subset(s) and their mechanisms that contribute to the development of LIT with the following Specific Aims: 1) Assess phenotypic and functional characteristics of suppressive HLN LIT B cell subset(s);2) Determine the mechanism(s) underlying LIT HLN B-cell-mediated induction of Treg cells;and 3) Determine if this inhibitory Breg represents recruitment of a pre-existing cell type into the HLNs or conversion from a pre-existing B cell subset. Insights gained from our proposed studies may elucidate important mechanisms underlying LIT and, ultimately, may help us learn how to similarly turn off airway inflammation in human asthmatics. Moreover, results of the above studies will yield new fundamental immunologic insights regarding B-cell regulation of T-cell function, which may have ramifications that extend well beyond asthma. PUBLIC HEALTH RELEVANCE: Allergic mice are able to turn off their asthma. They appear to make a specific type of B lymphocyte that is capable of creating regulatory T lymphocytes, which inhibit airway inflammation. Better understanding of this process in mice may help us to learn how to similarly turn off airway inflammation in human asthmatics.